Global Journal of Science Frontier Research, G: Bio-Tech & Genetics, Volume 22 Issue 2

using fluorescent in situ hybridization on the region that includes MDM2 and neighboring gene CPM 64 . Out of the four current theories on the formation of these neochromosomes 65 , two have evidence that they are likely the primary source of genetic heterogeneity within liposarcoma tumors (Figure 5). The first is that chromosome shattering events, called, “chromothripsis”, generated these neochromosomes. This suggests that this transformative event may have selected for cells with chr12 as their primary backbone, which promoted cell survival 59 . This selection would seem most likely due to the most amplified genes: MDM2 and CDK4 . MDM2 inhibits the tumor suppressor TP53, thereby circumventing the cell’s rescue signals during DNA damage to repair without proceeding through the cell cycle (G1 and G2 arrest) and any signals towards apoptosis that would cause the aberrant cell to die. CDK4 would allow for unimpeded and enhanced progression through the cell cycle. The manner in which these chromosome pieces are stitched together into a neochromosome appear random. Therefore, just as no two snowflakes are alike, it is conceivable that the number and content of neochromosomes in each liposarcoma cell would not be the same and would change with each cell division in the same way that mitochondrial DNA populations are altered in each daughter cell. The second theory is based on whole genome data of two DDLPS specimens that did not exhibit any features of chromothripsis 1 . In this study, the authors postulate that the neochromosomes are the result of progressive rearrangements and amplification. Both models are mutually exclusive and may delineate particular subsets of WDLPS and DDLPS. Following the generation of neochromosomes, either linear or circular breakage- fusion-bridge amplification (BFB) would lead to the multiple copies of the neochromosomes that are common to WDLPS and DDLPS 66 . Since BFB events do not always cause the exact same breaks within a chromosome, the daughter cell of any given neochromosome-containing parental cell is likely to be different (Figure 5). This was demonstrated using a CRISPR-based ecTag method in glioblastoma spheroids 67 . Amplification of oncogenes in extra chromosomal DNA may be the shortest route to heterogeneity than amplification of these genes within intact, autosomal chromosomes 67 . Hence, there is vast heterogeneity within the population of liposarcoma cells, supporting the early observations that both WDLPS and DDLPS contain all four CD34/CD36 adipose markers by flow cytometry, with each of the four populations present at different proportions 68 . The high level of heterogeneity is likely the reason treatment strategies are difficult to design. In addition, the triggers of transition or predominance of one subtype over the other is still unclear. Multiomic RNA and ATAC sequencing with spatial deconvolution may aid in tracking the mutation and environmental triggers as shown in recent studies in breast cancer and glioma 69 . 1 Year 2022 19 © 2022 Global Journals Global Journal of Science Frontier Research Volume XXII Issue ersion I VII ( G ) The Genomics of Liposarcoma: A Review and Commentary Figure 3: Neochromosome formation in liposarcoma. A. Chromothripsis leads to chromosome fragments that then circularize into neochromosomes. B. The Break-Fusion-Bridge pathway that generate rod neochromosomes. These rods have the potential to circularize into ring neochromosomes